Glaucoma management in pregnancy and post-partum
- 1 Summary
- 2 Introduction
- 3 Epidemiology
- 4 IOP changes and disease course
- 5 Medical treatment
- 6 Role of Laser
- 7 Surgery
- 8 Stages of pregnancy
- 9 References
Summary[edit | edit source]
The management of glaucoma during pregnancy and lactation presents unique challenges. Several glaucoma medications have potential adverse effects in the fetus or breastfeeding infant. These medications should be considered only after carefully balancing the potential dangers to the fetus or infant with the risk of worsening glaucoma in the mother. When medical treatment is employed, systemic absorption should be minimized through nasolacrimal duct occlusion or punctal plugging. Alternatives to medical treatment should be considered, including laser trabeculoplasty or observation off medical treatment.
Glaucoma surgery during pregnancy should be avoided, particularly in the first trimester when the risk of abortion and teratogenicity with anesthetics, sedative agents, and antimetabolites is highest. If glaucoma surgery is considered during pregnancy, special considerations should be taken regarding the use of antimetabolites, patient positioning, and the type of anesthesia administered.
Introduction[edit | edit source]
Glaucoma occurs most commonly in adults over the age of 40, but will occasionally occur in females of childbearing age. Often, women will have preexisting glaucoma which originally began in childhood (i.e. congenital glaucoma or anterior segment dysgenesis), or glaucoma secondary to uveitis, diabetes, etc. The treatment of glaucoma in and around pregnancy offers the unique challenge of balancing the risk of vision loss to the mother with potential harm to the fetus or newborn.
Here, we will discuss the management of glaucoma in and around pregnancy. Special consideration will be given to the pre-conception period, stage of pregnancy, and lactation period. Additionally, the unique risks of medical and surgical glaucoma treatment will be discussed, as will therapeutic alternatives to, and modifications of, standard medical treatment.
Epidemiology[edit | edit source]
Glaucoma has been reported to occur in roughly 2-3% of adults over the age of 40, though the prevalence increases substantially with age for all races and ethnicities. Few data exist regarding the prevalence of glaucoma prior to the age of 40, particularly in women of childbearing age. In one Japanese study, the prevalence of open angle glaucoma, defined by a visual field defect along with corroborating optic nerve findings, was 0.48%, 0.42%, and 0.73% among women aged 15-24,25-34, and 35-44, respectively.1 Additionally, women of childbearing age may have glaucoma acquired early in childhood (congenital glaucoma, anterior segment dysgenesis, or glaucoma after cataract formation), or glaucoma resulting from coexisting conditions presenting early in life, i.e. uveitis or diabetes.
IOP changes and disease course[edit | edit source]
Intraocular pressure typically decreases during pregnancy. In one study of pregnant women, the mean intraocular pressure of first trimester patients was on average 2 mmHg higher than that of third trimester patients.2 Potential mechanisms for this IOP reduction include greater aqueous outflow facility due to hormonal changes, decreased episcleral venous pressure from reduction of venous pressure in the upper limbs, and metabolic acidosis resulting from gestation. 3, 4 Specifically, increased progesterone and relaxin levels may decrease intraocular pressure and increase the coefficient of facility of aqueous outflow during the menstrual cycle and pregnancy. However, the extent to which these IOP changes should be anticipated in women with pre-existing glaucoma is unclear.
One small study of 15 women examined glaucoma progression during pregnancy. The authors found no increase in IOP or visual field progression in 57% of subjects. However, 18% of the women demonstrated progressive visual field loss, while an additional 18% demonstrated IOP elevation without visual field progression. Amongst the women with IOP increases, the mean increase was 10 mm Hg (range 1.3 mmHg to 22.5 mmHg). Many women in this second group required additional medication to control their IOP.5
Medical treatment[edit | edit source]
The safety of glaucoma medications in pregnancy has been classified by the United States Food and Drug Administration (FDA) based on evidence available from human and animal studies.
- Category A medications have strong evidence of safety based on human studies.
- Category B medications have varying and /or contradictory human and animal data. For example, a drug may be graded as Class B if animal studies showed some harm but human studies indicated safety, or if animal studies showed safety and no human studies were available.
- Category C is used to describe medicines which showed side effects in animal models, or where inadequate animal and human studies are available.
- Category D medications indicate human studies showing risk to the fetus.
- Category X drugs show strong evidence of birth defects.
Beta-blockers[edit | edit source]
Oral beta-blockers are categorized as class C medications in pregnancy. No specific categorization is available for topical beta blockers. Timolol can cross the placental barrier, thus resulting in fetal bradycardia and cardiac arrhythmia. Furthermore, beta-blockers can be secreted into breast milk and may cause similar effects in newborn infants. Indeed, one study of timolol use in children found plasma timolol levels ranging from 3.5 ng/ml in a five-year-old child to 34 ng/ml in a three-week-old infant.6 The same study also reported that the mean one-hour plasma timolol concentration was reduced by approximately 40% when punctal occlusion was performed. No formal studies have examined the relative effects of different timolol concentrations or dosing recommendations. However, minimal difference in IOP lowering has been noted for 0.25% timolol as compared to 0.5% timolol, and with 0.5% timolol dosed once daily, as compared to twice daily.
Alpha 2 Agonists [edit | edit source]
Brimonidine is classified as a Category B medication by the FDA. However, no well-controlled human studies have been done to rule out potential teratogenic effects. Additionally, brimonidine poses substantial risk to the newborn, having been reported to cause central nervous system depression and apnea. The drug penetrates the blood-brain barrier, and can cross the placenta and possibly excrete into breast milk, posing a real risk of apnea or hypotension in infants. Thus, even if brimonidine is used during pregnancy, it should be discontinued before labor and during breastfeeding to prevent potential fetal apnea in the infant.
Prostaglandin Analogues [edit | edit source]
Prostaglandin analogues are classified as Category C drugs and are associated with a high incidence of miscarriage in animal studies. Additionallly, a systematic review documented that oral or vaginal use of misoprostol in pregnancy is associated with an increased risk of Moebius syndrome and terminal transverse limb defects.7 Prostaglandins can also stimulate uterine contractions producing premature labor, though it is unclear whether the very low drug concentrations used in ophthalmic prostaglandin formulations are sufficient to elicit this side effect. Therefore, these medications should be used with caution. One small series followed 10 women exposed to latanoprost in the first trimester. Normal delivery occurred in 9 women without neonatal malformation, with one spontaneous abortion noted in a 46 year-old woman.8 Nonetheless, given the theoretical risk of premature delivery, prostaglandin analogues are not a choice for first-line medication in pregnancy.
Topical Carbonic Anhydrase Inhibitors [edit | edit source]
Brinzolamide is classified as a category C medication in pregnancy. In animal studies, there was a statistically lower fetal body weight with the oral medication (375 times the human ophthalmic dose). However, no organ malformations were seen even at this high dose.9
Dorzolamide is also classified as Category C medication. There were malformations of the vertebral bodies in rabbits exposed to dorzolamide during pregnancy, suggesting that brinzolamide may be a better alternative.10
No controlled reports of brinzolamide or dorzolamide exist in human pregnancy. As such, it may be used during pregnancy with caution when the possible benefit to the mother outweighs the theoretical risk to the fetus. It is uncertain if these medications are excreted in human milk, and thus their safety in breastfeeding is unknown.
Oral Carbonic Anhydrase Inhibitors [edit | edit source]
Acetazolamide is classified as a Category C medication. Systemic high dose carbonic anhydrase inhibitors in rats can result in forelimb anomalies.11 Also, a case report of neonatal sacrococcygeal teratoma was reported in a pregnant woman with acetazolamide use.12 On the other hand, there were no fetal adverse effects in 12 pregnant women who used oral acetazolamide for idiopathic intracranial hypertension management.13
Acetazolamide may also result in potential metabolic complications to the newborn or breast-feeding child. One case report exists of oral acetazolamide use during pregnancy crossing the placenta that caused transient renal tubular acidosis in a newborn.14 However, another case report demonstrated that acetazolamide plasma levels were low in infants exposed to the medication through breast milk.15 Therefore, acetazolamide is approved by the American Academy of Pediatrics(AAP) for use during nursing.16
Methazolamide is also classified as a Category C medication. Skeletal malformations have been reported in rats,but with dose 40 times higher than the human dose.17 No controlled investigations exist in human pregnant women. Details regarding whether the drug is excreted into human milk are unknown.
Minimizing systemic absorption of eye drops[edit | edit source]
All eye drops have potential systemic side effects which could possibly be avoided, or at least minimized, by reducing systemic absorption of the medication. Nasolacrimal occlusion and eyelids closure are easy techniques that can reduce the systemic adverse effects.18 Nasolacrimal occlusion is performed by using the fingertips to apply pressure over the puncta and canaliculi for 5 or more minutes to occlude nasolacrimal drainage. In one study, Systemic absorption of topical timolol was diminished 67% by nasolacrimal occlusion and 65% by eyelids closure.19
Additionally, both nasolacrimal occlusion and eyelids closure can increase eye-drug contact time resulting in higher intraocular drug concentrations, and less systemic absorption.19 Punctal plugging can reduce tear drainage and improve mean tear meniscus levels such that systemic absorption of drug is lowered.20,21 However, there are no direct studies on systemic absorption of glaucoma medications with punctal plugging. Nonetheless, this option should be discussed with women who choose to continue topical IOP-lowering therapy in and around pregnancy.
Role of Laser[edit | edit source]
Argon laser trabeculoplasty (ALT) or selective laser trabeculoplasty (SLT) may be considered in pregnant women to eliminate or reduce the number of necessary medications.
Unfortunately, ALT appears to be less effective in reducing IOP control in young patients.22 A retrospective study of Argon laser trabeculoplasty reported that 60% of lasered patients had uncontrolled IOP and required glaucoma surgery within two years following ALT.22 However, given the short time-frame of pregnancy, trabeculoplasty may still be considered in these patients.
One study demonstrated IOP reduction after cyclophotocoagulation in a pregnant patient with uveitic glaucoma. 23
Surgery[edit | edit source]
Surgical options[edit | edit source]
Glaucoma surgery could be considered during pregnancy if the patient has glaucoma progression despite the use of maximum safe medications. However, there are specific risks of glaucoma surgery in pregnant patients, including the risks of local and general anesthesia, and the need for post-operative medications. Additionally, glaucoma filtration surgery in pregnant patients may be at relatively higher risk of failure because of their young patient age 24 and contraindicated antimetabolite usage.
Anesthetic Concerns of Surgery[edit | edit source]
Surgical anesthesia in pregnancy poses risks to both the mother and fetus. Maternal physiology is altered such that plasma volume and cardiac output are greater, and peripheral vascular resistance is reduced, thus lowering blood pressure. Additionally, supine position in the second and third trimester can induce profound hypotension due to aortic and vena caval compression by the uterus. Ideally, the pregnant women should be placed on their left side, though this may complicate positioning of the eye for surgery. The patient should be well hydrated and oxygenated before anesthesia induction to prevent maternal hypotension and hypoxia.25
In pregnancy, minute ventilation and oxygen consumption increase, while functional residual capacity decrease. Thus, the pregnant women can develop hypoxia and hypercapnia more quickly. Furthermore, airway management is hard in pregnant patients with breast enlargement, weight gain, and laryngeal edema.25 The risk for gastric acid aspiration through anesthesia induction is raised in gravid patients as gastroesophageal sphincter tone and intestinal motility are reduced. Full stomach precaution techniques have to be performed to reduce the risk of gastric acid aspiration.25
For general anesthesia cases, narcotics, paralyzing agents, and inhaled anesthetic agents can influence to the fetus. Thiopental is a narcotic agent that has been shown to not have a teratogenic effect in animal or human studies.25 Succinylcholine is a paralytic agent that is often used before intubation. High dose exposure of this agent may affect neuromuscular paralysis in newborn.25 Halothane and nitrous oxide are inhaled anesthesics that have been reported to result in growth retardation and congenital anomalies in animal studies. However, there are no well controlled human studies that have reported teratogenic effects of these agents.25 The side effects of these medications make local anesthesia much more preferable, if at all possible.
Regarding local anesthesia, fetal bradycardia was reported when applying bupivacaine in pregnancy, but lidocaine has not been related with any adverse effect in the fetus.26 If nursing patients need to undergo glaucoma surgery, lidocaine should be administrated immediately after nursing to reduce the amount of lidocaine in breast milk.27
Surgical Positioning[edit | edit source]
Supine position in second and third trimester gestation can induce profound systemic hypotension due to aortic and vena caval compression by the uterus. Consideration should be given to rotating the patients hips, abdomen, and thighs while maintaining a normal head position for ophthalmic surgery.
For maternal safety, uterine displacement ought to be considered to prevent systemic hypotension. Because of diminishing of gastroesophageal sphincter tone in pregnant patients, full stomach precaution techniques should be performed to reduce the risk of gastric acid aspiration.
Intraoperative noninvasive fetal monitoring should be considered in major surgery, but may not be necessary for the short duration of glaucoma surgery. Teratogenic effects in anesthetic or sedative agents remain a possible risk. Avoiding surgery in first trimester may decrease the risk of teratogenicity and spontaneous abortion.28
The risk of preterm labor or abortion is increased with surgery during pregnancy. Topographic monitoring in the postoperative period may detect preterm labour.29 Fetal heart rate monitoring is a good detector of fetal asphyxia during surgery.29 In addition, fetal ultrasound before and immediately after surgery is reasonable to examine the gross anatomical abnormalities of the fetus.
Intra- and Peri-Operative Medications[edit | edit source]
Mitomycin C is an antifibrotic agent which is frequently applied in glaucoma surgery. A decrease of mean litter size and body weight and an increase of exencephaly in second gestation mice were associated with mitomycin use.29 There are no studies reporting the teratogenic effect of this drug in the human fetus, though the mechanism of action of the drug strongly suggests a possible teratogenic risk.
Fluorouracil is an antimetabolite that has been associated with several congenital anomalies in mothers who had obtained intravenous 5-fluorouracil in first trimester.30 The risk of subconjunctival administration is not known.
The use of antimetabolite agents for glaucoma surgery ought to be avoided in gravid patients because of the potential teratogenic effects.31
Topical antibiotics are commonly used after glaucoma surgery, and the risks of many antibiotics in pregnancy have been described, mostly with oral administration.
Erythromycin is the oldest of macrolides, which poorly passes through the placenta. This medication is classified as category B. There are no studies relating erythromycin and congenital anomalies.25 There are also no reports of adverse effects of the macrolides in breastfeeding.32 Tetracyclines are classified as a category D medications that can cross placenta quickly. They may cause brown discoloration of the deciduous teeth and suppress of bone growth when applying after fifteen weeks of pregnancy, but there is no data of teeth discoloration with their use in nursing mothers.32
Aminoglycosides are classified as a category D medications. Gentamicin, neomycin and tobramycin are the aminoglycosides which rapidly cross the placenta. There is no evidence that the aminoglycosides cause teratogenic effects in the fetus with the exception of possible eight cranial nerve damage.25 Tobramycin can be detected only in limited amounts in mother’s milk.32
Chloramphenicol is not advised for using in pregnancy because it has been linked with the gray baby syndrome25
Fluoroquinolones are classified as a category C medications. Ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin are all fluoroquinolones that cross the placenta. Animal studies have indicated that quinolone can cause cartilage damage of the fetus. Nevertheless, one study of the first trimester pregnant women who were giving fluoroquinolones have shown no significant increase of congenital anomalies.32 Regarding breastfeeding, no reports have shown levofloxacin, gatifloxacin and moxifloxacin passing into the breastmilk. In animal experiments, quinolone can damage the cartilage of the joint.32
In summary, erythromycin seems to have less adverse effect in pregnancy and lactation period, and should be strongly considered as the antibiotic of choice after glaucoma surgery in the pregnant or breast-feeding woman.
Corticosteroids are classified as a category C medication. Topical corticosteroids are nearly always used after glaucoma surgery. All systemic glucocorticoids cross the placenta. Prednisolone and methylprednisolone cross the placenta less than betamethasone and dexamethasone and may have less of an effect on the fetus.32 Some studies have been published suggesting the absence of fetal teratogenicity with oral steroids.31 Given the strong tendency to use topical steroids after glaucoma surgery, and the absence of clear complications associated with these medicines, these medicines can be used in the pregnant or breastfeeding woman.
Atropine is classified as a category C medication. Topical atropine is occasionally used postoperatively in glaucoma surgery. Atropine can affect fetal heart rate, though the effect may be less likely with ophthalmic dose.25
For all topical medications used in conjunction with glaucoma surgery, punctal occlusion and eyelid closure should be considered to decrease systemic absorption of the medication.
Stages of pregnancy[edit | edit source]
Pre-Conception[edit | edit source]
Ideally, a discussion of the treatment plan of a woman’s glaucoma should be initiated before pregnancy begins. In this way, the adverse effects of medications can be prevented during the first trimester, when most organogenesis is occurring. Additionally, alternate effective methods to lower IOP (including surgery if necessary) can be explored or achieved prior to pregnancy beginning. Women of childbearing age should inform their doctor immediately should they suspect they are pregnant, or if they are planning to start or add to their family.
First Trimester[edit | edit source]
A discussion of the risks of medication and the best strategy for IOP-lowering should occur as soon as pregnancy is noted, as organogenesis has often begun when pregnancy is first identified, and medications taken during organogenesis can result in birth defects. Pregnancy discussions should include a discussion of medication concentration/dosage, methods to minimize systemic drug absorption, and if medication can be withheld for parts of the pregnancy.
Brimonidine, a Category B drug, may be the safest option for the first trimester. Other anti glaucoma medications such as beta-blocker, prostaglandins and carbonic anhydrase inhibitors should be avoided when possible in first trimester to reduce potential teratogenic effects or premature abortion. Discussions with the patient may include observation off treatment in this critical period.
For glaucoma surgery, anesthetics, sedative agents, and antimetabolites are all possible teratogenic agents. Therefore, avoiding surgery in first trimester may decrease the risk of teratogenicity and spontaneous abortion.
Second Trimester[edit | edit source]
In second trimester, brimonidine can be applied and beta-blockers can be used with regular fetal heart rate and fetal growth monitoring. If prostaglandin analogues are used, premature labor symptoms and signs should be described to the patient, and the medication should be stopped if such symptoms are noted. When topical or oral carbonic anhydrase inhibitors are used, fetal growth retardation monitoring may be considered.
Third Trimester[edit | edit source]
Brimonidine, beta-blocker, or topical carbonic anhydrase inhibitors, can be used with caution. Avoidance of prostaglandins may decrease the risk of premature labor, which is particularly important early in the third trimester. Late in the third trimester, brimonidine should be discontinued because it can induce central nervous system depression in newborns. Topical carbonic anhydrase inhibitors may be the optimal choice in this period.
Glaucoma surgery can be performed with caution in second and third trimester if the patients have a strong indication for the procedure. However, anesthetics, sedative agents, and antimetabolites still have potential risk for the fetus. Additionally, uterine displacement ought to be performed to prevent maternal hypotension that can induce fetal asphyxia.
Argon laser trabeculoplasty(ALT)or selective laser trabeculoplasty (SLT)is an alternative glaucoma treatment that can be performed in all trimesters. ALT or SLT may be less effective for long term IOP control, but may result in short-term IOP control until the end of pregnancy.
Postpartum[edit | edit source]
Carbonic anhydrase inhibitors and beta-blockers are certified by the American Academy of Pediatrics for use during nursing. However, low doses of these medications should be considered when used in the breast feeding period. Brimonidine is contraindicated for use in lactating mothers due to the risk of central nervous system depression in the newborn.
References[edit | edit source]
1. Yoshidaa M, Okadaa E, and Mizukib N. Age-specific prevalence of open-angle glaucoma and its relationship to refraction among more than 60,000 asymptomatic Japanese subjects. J Clin Epi 2001;54:1151-1158.
2. Calbert IP,Sheila MG. Ocular hypotensive effect of late pregnancy with and without high blood pressure. Br J Ophthalmol 1985;69:117-119
3. Becker B, Friedenwald JS. Clinical aqueous outflow. Arch Ophthalmol 1953;50:557–71.
4. Gillian DP, Stephen JH M. Hormonal influence in simple glaucoma. A preliminary report. Br J Ophthalmol 1963;47:129-137.
5. Stacey CB, Teresa CC, Thomas H,et al. The course of glaucoma during pregnancy. Arch Ophthalmol 2006;124:1089-1094.
6. Passo MS, Palmer EA, Van Buskirk EM. Plasma timolol in glaucoma patients. Ophthalmology. 1984 Nov;91(11):1361-3.
7. Tatiane da Silva Dal Pizzol , Fl´avia Pozzobon Knop,and Sotero Serrate Mengue. Prenatal exposure to misoprostol and congenital anomalies:Systematic review and meta-analysis. Reproductive Toxicology 2006;22:666–671.
8. Marco De S, Angela L,Brigida C, et al. Latanoprost exposure in pregnancy. Am J Ophthalmol 2004;138:305-306.
9. Manufacturer’s Information: Azopt product monograph. Texas: Alcon Ophthalmics, Fort Worth, April 1998.
10. Manufacturer’s Information: Trusopt product monograph. Pennsylvania: Merck & Co Inc, West Point, February 1999.
11. Holmes LB, Kawanishi H, Munoz A. Acetazolamide:maternal toxicity, pattern of malformations,and litter effect. Teratology 1988; 37: 335–342.
12. Worsham F Jr, Beckman EN, Mitchell EH. Sacrococcygeal teratoma in a neonate association with maternal use of acetazolamide. JAMA 1978; 240: 251–252.
13. Lee AG, Pless M, Falardeau J, Capozzoli T,Wall M, Kardon RH. The use of acetazolamide in idiopathic intracranial hypertension during pregnancy. Am J Ophthalmol 2005; 139: 855–859.
14. Ozawa H, Azuma E, Shindo K, Higashigawa M, Mukouhara R,Komada Y. Transient renal tubular acidosis in a neonate following transplacental acetazolamide. Eur J Pediatr 2001;160:321-2.
15. Soderman P, Hartvig F. Acetazolamide excretion into human breast milk. Br J clin Pharmac 1984;17:599-600.
16. American Academy of Pediatrics Committee on Drugs:Transfer of drugs and other chemicals into human milk[published erratum appears in Pediatrics 1990 May;85(5):847] [see comments]. Pediatrics 84:924–36, 1989.
17. Manufacturer’s Information: Methazolamide. Georgia: Effcon laboratories, INC.
18. Flach AJ. The Importance of Eyelid Closure and Nasolacrimal Occlusion Following the Ocular Instillation of Topical Glaucoma Medications, and the Need for the Universal Inclusion of One of these Techniques in All Patient
Treatments and Clinical Studies Trans Am Ophthalmol Soc. 2008 December; 106: 138–148.
19. Zimmerman TJ, Kooner KS, Kandarakis AS. Improving the Therapeutic Index of Topically Applied Ocular Drugs. Arch Ophthalmol 1984;102:551-553.
20. Lindén C, Alm A. The effect of reduced tear drainage on corneal and aqueous concentrations of topically applied fluorescein. Acta ophthalmol 1990;68:633-8,
21. Burgess PI, Koay P,and Clark P. SmartPlug versus silicone punctal plug therapy for dry eye: a prospective randomized trial. Cornea 2008;27:391-4.
22. Safran MJ, Robin AL, Pollack IP. Argon laser trabeculoplasty in younger patients with primary open-angle glaucoma. Am J Ophthalmol. 1984;97:292-295.
23. M Wertheim, D C Broadway. Cyclodiode laser therapy to control intraocular pressure during pregnancy. Br J Ophthalmol 2002;86:1318-1319.
24. The Advanced Glaucoma Intervention Study (AGIS) 11. Risk factors for failure of trabeculectomy and argon laser trabeculoplasty. Am J Ophthalmol 2002;134:481-489.
25. Little BB. Drugs and Pregnancy, A handbook 2006. Oxford University Press Inc.
26. Moore PA. Selecting drugs for the pregnant dental patient. J Am Dent Assoc 1998;129:1281–6.
27. Sandra M. J, Mary M and Sharon F. Management of Glaucoma in Pregnancy and Lactation. Survey of ophthalmology 2001;45:449-454.
28. Mark A.R. Management of anesthesia for the pregnant surgical patient. Anesthesiology 1999;91:1159-1163.
29. Van De Velde M, De Buck F. Anesthesia for non-obstetric surgery in the pregnant patient. Minerva Anesthesiol 2007;73:235-240.
30. Abou-Tarboush FM, Al-Himidi AR, and El-Bana AA. Long term teratogenic effects of mitomycin c on the second gestation in mice. J King Saud Univ. 1994;6:33-40.
31. Anne L. C, Sameh M, and Deborah K. Medical Therapy in Pregnancy. J Glaucoma 2005;14:414-416.
32. Schaefer C, Peters P, and Miller RK. Drugs During Pregnancy and Lactation. Second edition Elsevier BV.